Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Interstitial leukocyte migration and immune function

Nature Immunology volume 9, pages 960–969 (2008)Cite this article

Abstract

The trafficking of leukocytes into and within lymphoid and peripheral tissues is central to immune cell development, immunosurveillance and effector function. Interstitial leukocyte trafficking is the result of amoeboid polarization and migration, guided by soluble or tissue-bound chemoattractant signals for positioning and local arrest. In contrast to other migration modes, amoeboid movement is particularly suited for scanning cellular networks and tissues. Here, we review mechanisms of leukocyte migration and sensing involved in diapedesis, tissue-based interstitial migration and egress, immune cell positioning in inflammation, and emerging therapeutic interference strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Morphology, surface receptors and signaling in amoeboid leukocyte migration.
Figure 2: Principles of leukocyte–substrate interactions and guidance.
Figure 3: Leukocyte migration in different environments in vivo.
Figure 4: A balance between amoeboid migration, adhesive arrest and intermediate states.

Similar content being viewed by others

References

  1. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    CAS  PubMed  Google Scholar 

  2. Miller, M.J., Hejazi, A.S., Wei, S.H., Cahalan, M.D. & Parker, I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc. Natl. Acad. Sci. USA 101, 998–1003 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller, M.J., Safrina, O., Parker, I. & Cahalan, M.D. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Mempel, T.R., Henrickson, S.E. & Von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).

    CAS  PubMed  Google Scholar 

  5. Bhakta, N.R., Oh, D.Y. & Lewis, R.S. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat. Immunol. 6, 143–151 (2005).

    CAS  PubMed  Google Scholar 

  6. Ley, K., Laudanna, C., Cybulsky, M.I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    CAS  PubMed  Google Scholar 

  7. Heit, B. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nat. Immunol. 9, 743–752 (2008).

    CAS  PubMed  Google Scholar 

  8. Mackay, C.R. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nat Immunol. 9, 988–998 (2008).

    CAS  PubMed  Google Scholar 

  9. Friedl, P. Prespecification and plasticity: shifting mechanisms of cell migration. Curr. Opin. Cell Biol. 16, 14–23 (2004).

    CAS  PubMed  Google Scholar 

  10. Wolf, K., Muller, R., Borgmann, S., Brocker, E.B. & Friedl, P. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood 102, 3262–3269 (2003).

    CAS  PubMed  Google Scholar 

  11. Wolf, K. et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat. Cell Biol. 9, 893–904 (2007).

    CAS  PubMed  Google Scholar 

  12. Friedl, P. et al. Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res. 55, 4557–4560 (1995).

    CAS  PubMed  Google Scholar 

  13. Friedl, P., Hegerfeldt, Y. & Tusch, M. Collective cell migration in morphogenesis and cancer. Int. J. Dev. Biol. 48, 441–449 (2004).

    CAS  PubMed  Google Scholar 

  14. Friedl, P. & Brocker, E.B. TCR triggering on the move: diversity of T-cell interactions with antigen-presenting cells. Immunol. Rev. 186, 83–89 (2002).

    CAS  PubMed  Google Scholar 

  15. Wei, X., Tromberg, B.J. & Cahalan, M.D. Mapping the sensitivity of T cells with an optical trap: polarity and minimal number of receptors for Ca2+ signaling. Proc. Natl. Acad. Sci. USA 96, 8471–8476 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Stanley, P. et al. Intermediate-affinity LFA-1 binds alpha-actinin-1 to control migration at the leading edge of the T cell. EMBO J. 27, 62–75 (2008).

    CAS  PubMed  Google Scholar 

  17. Negulescu, P.A., Krasieva, T.B., Khan, A., Kerschbaum, H.H. & Cahalan, M.D. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4, 421–430 (1996).

    CAS  PubMed  Google Scholar 

  18. Beemiller, P., Hoppe, A.D. & Swanson, J.A. A phosphatidylinositol-3-kinase-dependent signal transition regulates ARF1 and ARF6 during Fcγ receptor-mediated phagocytosis. PLoS Biol. 4, e162 (2006).

    PubMed  PubMed Central  Google Scholar 

  19. Pytowski, B., Maxfield, F.R. & Michl, J. Fc and C3bi receptors and the differentiation antigen BH2-Ag are randomly distributed in the plasma membrane of locomoting neutrophils. J. Cell Biol. 110, 661–668 (1990).

    CAS  PubMed  Google Scholar 

  20. Servant, G., Weiner, O.D., Neptune, E.R., Sedat, J.W. & Bourne, H.R. Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. Mol. Biol. Cell 10, 1163–1178 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fernandez-Segura, E., Garcia, J.M. & Campos, A. Topographic distribution of CD18 integrin on human neutrophils as related to shape changes and movement induced by chemotactic peptide and phorbol esters. Cell. Immunol. 171, 120–125 (1996).

    CAS  PubMed  Google Scholar 

  22. Friedl, P., Entschladen, F., Conrad, C., Niggemann, B. & Zanker, K.S. CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. Eur. J. Immunol. 28, 2331–2343 (1998).

    CAS  PubMed  Google Scholar 

  23. Laskin, D.L., Kimura, T., Sakakibara, S., Riley, D.J. & Berg, R.A. Chemotactic activity of collagen-like polypeptides for human peripheral blood neutrophils. J. Leukoc. Biol. 39, 255–266 (1986).

    CAS  PubMed  Google Scholar 

  24. Senior, R.M., Gresham, H.D., Griffin, G.L., Brown, E.J. & Chung, A.E. Entactin stimulates neutrophil adhesion and chemotaxis through interactions between its Arg-Gly-Asp (RGD) domain and the leukocyte response integrin. J. Clin. Invest. 90, 2251–2257 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Adair-Kirk, T.L. et al. A site on laminin alpha 5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis. J. Immunol. 171, 398–406 (2003).

    CAS  PubMed  Google Scholar 

  26. Thelen, M. & Stein, J.V. How chemokines invite leukocytes to dance. Nat Immunol. 9, 953–959 (2008).

    CAS  PubMed  Google Scholar 

  27. Marone, R., Cmiljanovic, V., Giese, B. & Wymann, M.P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta 1784, 159–185 (2008).

    CAS  PubMed  Google Scholar 

  28. Stambolic, V. & Woodgett, J.R. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol. 16, 461–466 (2006).

    CAS  PubMed  Google Scholar 

  29. Enomoto, A. et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell 9, 389–402 (2005).

    CAS  PubMed  Google Scholar 

  30. Rommel, C., Camps, M. & Ji, H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat. Rev. Immunol. 7, 191–201 (2007).

    CAS  PubMed  Google Scholar 

  31. Nombela-Arrieta, C. et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 21, 429–441 (2004).

    CAS  PubMed  Google Scholar 

  32. Ibarra, N., Pollitt, A. & Insall, R.H. Regulation of actin assembly by SCAR/WAVE proteins. Biochem. Soc. Trans. 33, 1243–1246 (2005).

    CAS  PubMed  Google Scholar 

  33. Machesky, L.M. et al. Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. Proc. Natl. Acad. Sci. USA 96, 3739–3744 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Charest, P.G. & Firtel, R.A. Feedback signaling controls leading-edge formation during chemotaxis. Curr. Opin. Genet. Dev. 16, 339–347 (2006).

    CAS  PubMed  Google Scholar 

  35. Bendix, P.M. et al. A quantitative analysis of contractility in active cytoskeletal protein networks. Biophys. J. 94, 3126–3136 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Eddy, R.J., Pierini, L.M. & Maxfield, F.R. Microtubule asymmetry during neutrophil polarization and migration. Mol. Biol. Cell 13, 4470–4483 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lammermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

    PubMed  Google Scholar 

  38. Ferguson, G.J. et al. PI(3)Kγ has an important context-dependent role in neutrophil chemokinesis. Nat. Cell Biol. 9, 86–91 (2007).

    CAS  PubMed  Google Scholar 

  39. Li, Z. et al. Regulation of PTEN by Rho small GTPases. Nat. Cell Biol. 7, 399–404 (2005).

    CAS  PubMed  Google Scholar 

  40. Campello, S. et al. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 203, 2879–2886 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Friedl, P. & Brocker, E.B. T cell migration in three-dimensional extracellular matrix: guidance by polarity and sensations. Dev. Immunol. 7, 249–266 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mandeville, J.T., Lawson, M.A. & Maxfield, F.R. Dynamic imaging of neutrophil migration in three dimensions: mechanical interactions between cells and matrix. J. Leukoc. Biol. 61, 188–200 (1997).

    CAS  PubMed  Google Scholar 

  43. Wolf, K. & Friedl, P. Mapping proteolytic cancer cell-extracellular matrix interfaces. Clin. Exp. Metastasis published online, doi: 10.1007/s10585-008-9190-2 (4 July 2008).

  44. Leppert, D., Waubant, E., Galardy, R., Bunnett, N.W. & Hauser, S.L. T cell gelatinases mediate basement membrane transmigration in vitro. J. Immunol. 154, 4379–4389 (1995).

    CAS  PubMed  Google Scholar 

  45. Wang, S. et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J. Exp. Med. 203, 1519–1532 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. McQuibban, G.A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000).

    CAS  PubMed  Google Scholar 

  47. Murphy, G., Murthy, A. & Khokha, R. Clipping, shedding and RIPping keep immunity on cue. Trends Immunol. 29, 75–82 (2008).

    CAS  PubMed  Google Scholar 

  48. Friedl, P. & Wolf, K. Proteolytic and non-proteolytic migration in tumor cells and leukocytes. Biochem. Soc. Symp. 70 277–285 (2003).

    CAS  Google Scholar 

  49. Pals, S.T., de Gorter, D.J. & Spaargaren, M. Lymphoma dissemination: the other face of lymphocyte homing. Blood 110, 3102–3111 (2007).

    CAS  PubMed  Google Scholar 

  50. Gunzer, M., Kampgen, E., Brocker, E.B., Zanker, K.S. & Friedl, P. Migration of dendritic cells in 3D-collagen lattices. Visualisation of dynamic interactions with the substratum and the distribution of surface structures via a novel confocal reflection imaging technique. Adv. Exp. Med. Biol. 417, 97–103 (1997).

    CAS  PubMed  Google Scholar 

  51. De Nichilo, M.O. & Burns, G.F. Granulocyte-macrophage and macrophage colony-stimulating factors differentially regulate alpha v integrin expression on cultured human macrophages. Proc. Natl. Acad. Sci. USA 90, 2517–2521 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. McNally, A.K. & Anderson, J.M. β1 and β2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am. J. Pathol. 160, 621–630 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chung, A., Gao, Q. & Kao, W.J. Macrophage matrix metalloproteinase-2/-9 gene and protein expression following adhesion to ECM-derived multifunctional matrices via integrin complexation. Biomaterials 28, 285–298 (2007).

    CAS  PubMed  Google Scholar 

  54. Bromley, S.K., Mempel, T.R. & Luster, A.D. Orchestrating the orchestrators: chemokine control of T cell trafficking. Nat. Immunol. 9, 970–980 (2008).

    CAS  PubMed  Google Scholar 

  55. Dangerfield, J., Larbi, K.Y., Huang, M.T., Dewar, A. & Nourshargh, S. PECAM-1 (CD31) homophilic interaction up-regulates α6β1 on transmigrated neutrophils in vivo and plays a functional role in the ability of α6 integrins to mediate leukocyte migration through the perivascular basement membrane. J. Exp. Med. 196, 1201–1211 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Young, R.E., Voisin, M.B., Wang, S., Dangerfield, J. & Nourshargh, S. Role of neutrophil elastase in LTB4-induced neutrophil transmigration in vivo assessed with a specific inhibitor and neutrophil elastase deficient mice. Br. J. Pharmacol. 151, 628–637 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. El-Shabrawi, Y., Walch, A., Hermann, J., Egger, G. & Foster, C.S. Inhibition of MMP-dependent chemotaxis and amelioration of experimental autoimmune uveitis with a selective metalloproteinase-2 and -9 inhibitor. J. Neuroimmunol. 155, 13–20 (2004).

    CAS  PubMed  Google Scholar 

  58. Agrawal, S. et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J. Exp. Med. 203, 1007–1019 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Steadman, R. et al. Human neutrophils do not degrade major basement membrane components during chemotactic migration. Int. J. Biochem. Cell Biol. 29, 993–1004 (1997).

    PubMed  Google Scholar 

  60. Thureson-Klein, A., Hedqvist, P. & Lindbom, L. Leukocyte diapedesis and plasma extravasation after leukotriene B4: lack of structural injury to the endothelium. Tissue Cell 18, 1–12 (1986).

    CAS  PubMed  Google Scholar 

  61. Roussel, E. & Gingras, M.C. Transendothelial migration induces rapid expression on neutrophils of granule-release VLA6 used for tissue infiltration. J. Leukoc. Biol. 62, 356–362 (1997).

    CAS  PubMed  Google Scholar 

  62. Berg, L.P. et al. Functional consequences of noncognate interactions between CD4+ memory T lymphocytes and the endothelium. J. Immunol. 168, 3227–3234 (2002).

    CAS  PubMed  Google Scholar 

  63. Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lindquist, R.L. et al. Visualizing dendritic cell networks in vivo. Nat. Immunol. 5, 1243–1250 (2004).

    CAS  PubMed  Google Scholar 

  65. Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    CAS  PubMed  Google Scholar 

  66. Ansel, K.M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    CAS  PubMed  Google Scholar 

  67. Mempel, T.R., Scimone, M.L., Mora, J.R. & von Andrian, U.H. In vivo imaging of leukocyte trafficking in blood vessels and tissues. Curr. Opin. Immunol. 16, 406–417 (2004).

    CAS  PubMed  Google Scholar 

  68. Friedman, R.S., Jacobelli, J. & Krummel, M.F. Surface-bound chemokines capture and prime T cells for synapse formation. Nat. Immunol. 7, 1101–1108 (2006).

    CAS  PubMed  Google Scholar 

  69. Woolf, E. et al. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat. Immunol. 8, 1076–1085 (2007).

    CAS  PubMed  Google Scholar 

  70. Dustin, M.L., Bromley, S.K., Kan, Z., Peterson, D.A. & Unanue, E.R. Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl. Acad. Sci. USA 94, 3909–3913 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gunzer, M. et al. A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo. Blood 104, 2801–2809 (2004).

    CAS  PubMed  Google Scholar 

  72. Friedl, P., den Boer, A.T. & Gunzer, M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat. Rev. Immunol. 5, 532–545 (2005).

    CAS  PubMed  Google Scholar 

  73. Shakhar, G. et al. Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat. Immunol. 6, 707–714 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wei, S.H. et al. Ca2+ signals in CD4+ T cells during early contacts with antigen-bearing dendritic cells in lymph node. J. Immunol. 179, 1586–1594 (2007).

    CAS  PubMed  Google Scholar 

  75. Henrickson, S.E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat. Immunol. 9, 282–291 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lu, T.T. & Cyster, J.G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).

    CAS  PubMed  Google Scholar 

  77. Huse, M., Lillemeier, B.F., Kuhns, M.S., Chen, D.S. & Davis, M.M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006).

    CAS  PubMed  Google Scholar 

  78. Sims, T.N. et al. Opposing effects of PKCθ and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129, 773–785 (2007).

    CAS  PubMed  Google Scholar 

  79. Nobile, C. et al. Cognate CD4+ T-cell-dendritic cell interactions induce migration of immature dendritic cells through dissolution of their podosomes. Blood 111, 3579–3590 (2008).

    CAS  PubMed  Google Scholar 

  80. Chieppa, M., Rescigno, M., Huang, A.Y. & Germain, R.N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Schon, M.P., Schon, M., Parker, C.M. & Williams, I.R. Dendritic epidermal T cells (DETC) are diminished in integrin αE(CD103)-deficient mice. J. Invest. Dermatol. 119, 190–193 (2002).

    PubMed  Google Scholar 

  82. Cepek, K.L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αE β7 integrin. Nature 372, 190–193 (1994).

    CAS  PubMed  Google Scholar 

  83. Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).

    PubMed  PubMed Central  Google Scholar 

  84. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction. Nature 440, 890–895 (2006).

    CAS  PubMed  Google Scholar 

  85. Gunzer, M. et al. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13, 323–332 (2000).

    CAS  PubMed  Google Scholar 

  86. Cahalan, M.D. & Parker, I. Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Annu. Rev. Immunol. 26, 585–626 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Pham, T.H., Okada, T., Matloubian, M., Lo, C.G. & Cyster, J.G. S1P1 receptor signaling overrides retention mediated by Gαi–coupled receptors to promote T cell egress. Immunity 28, 122–133 (2008).

    CAS  PubMed  Google Scholar 

  88. Arita, M. et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912–3917 (2007).

    CAS  PubMed  Google Scholar 

  89. Schwab, J.M., Chiang, N., Arita, M. & Serhan, C.N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Van Lint, P. & Libert, C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J. Leukoc. Biol. 82, 1375–1381 (2007).

    CAS  PubMed  Google Scholar 

  91. Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    CAS  PubMed  Google Scholar 

  92. Stoitzner, P., Pfaller, K., Stossel, H. & Romani, N. A close-up view of migrating Langerhans cells in the skin. J. Invest. Dermatol. 118, 117–125 (2002).

    CAS  PubMed  Google Scholar 

  93. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat. Immunol. 5, 713–720 (2004).

    CAS  PubMed  Google Scholar 

  94. Debes, G.F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6, 889–894 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ledgerwood, L.G. et al. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat. Immunol. 9, 42–53 (2008).

    CAS  PubMed  Google Scholar 

  96. Martín-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003).

    PubMed  PubMed Central  Google Scholar 

  97. Marttila-Ichihara, F. et al. Macrophage mannose receptor on lymphatics controls cell trafficking. Blood 112, 64–72 (2008).

    CAS  PubMed  Google Scholar 

  98. Salmi, M., Koskinen, K., Henttinen, T., Elima, K. & Jalkanen, S. CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood 104, 3849–3857 (2004).

    CAS  PubMed  Google Scholar 

  99. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    CAS  PubMed  Google Scholar 

  100. Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).

    PubMed  PubMed Central  Google Scholar 

  101. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    CAS  PubMed  Google Scholar 

  102. Kratz, A., Campos-Neto, A., Hanson, M.S. & Ruddle, N.H. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183, 1461–1472 (1996).

    CAS  PubMed  Google Scholar 

  103. Gal, I. et al. Visualization and in situ analysis of leukocyte trafficking into the ankle joint in a systemic murine model of rheumatoid arthritis. Arthritis Rheum. 52, 3269–3278 (2005).

    PubMed  Google Scholar 

  104. Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    CAS  PubMed  Google Scholar 

  105. Gressner, A.M. & Weiskirchen, R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J. Cell. Mol. Med. 10, 76–99 (2006).

    CAS  PubMed  Google Scholar 

  106. Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med. 11, 936–943 (2005).

    CAS  PubMed  Google Scholar 

  107. Mathis, S., Jala, V.R. & Haribabu, B. Role of leukotriene B4 receptors in rheumatoid arthritis. Autoimmun. Rev. 7, 12–17 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Boissonnas, A., Fetler, L., Zeelenberg, I.S., Hugues, S. & Amigorena, S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J. Exp. Med. 204, 345–356 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Breart, B., Lemaitre, F., Celli, S. & Bousso, P. Two-photon imaging of intratumoral CD8 T cell cytotoxic activity during adoptive T cell therapy in mice. J. Clin. Invest. 118, 1390–1397 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Jaaskelainen, J. et al. Migration of recombinant IL-2-activated T and natural killer cells in the intercellular space of human H-2 glioma spheroids in vitro. A study on adhesion molecules involved. J. Immunol. 149, 260–268 (1992).

    CAS  PubMed  Google Scholar 

  111. O'Hayre, M., Salanga, C.L., Handel, T.M. & Allen, S.J. Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem. J. 409, 635–649 (2008).

    CAS  PubMed  Google Scholar 

  112. Silzle, T. et al. Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur. J. Immunol. 33, 1311–1320 (2003).

    CAS  PubMed  Google Scholar 

  113. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  PubMed  Google Scholar 

  114. Zhang, T. et al. CXC chemokine ligand 12 (stromal cell-derived factor 1 alpha) and CXCR4-dependent migration of CTLs toward melanoma cells in organotypic culture. J. Immunol. 174, 5856–5863 (2005).

    CAS  PubMed  Google Scholar 

  115. Zhang, B., Chan, Y.K., Lu, B., Diamond, M.S. & Klein, R.S. CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during West Nile virus encephalitis. J. Immunol. 180, 2641–2649 (2008).

    CAS  PubMed  Google Scholar 

  116. Brown, C.E. et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J. Immunol. 179, 3332–3341 (2007).

    CAS  PubMed  Google Scholar 

  117. Winter, H. et al. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines. J. Transl. Med. 5, 56 (2007).

    PubMed  PubMed Central  Google Scholar 

  118. Mrass, P. et al. Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J. Exp. Med. 203, 2749–2761 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kawakami, N. et al. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med. 201, 1805–1814 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Le Floc'h, A. et al. αEβ7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J. Exp. Med. 204, 559–570 (2007).

    CAS  PubMed  Google Scholar 

  121. Thomsen, A.R., Nansen, A., Madsen, A.N., Bartholdy, C. & Christensen, J.P. Regulation of T cell migration during viral infection: role of adhesion molecules and chemokines. Immunol. Lett. 85, 119–127 (2003).

    CAS  PubMed  Google Scholar 

  122. Applegate, K.G., Balch, C.M. & Pellis, N.R. In vitro migration of lymphocytes through collagen matrix: arrested locomotion in tumor-infiltrating lymphocytes. Cancer Res. 50, 7153–7158 (1990).

    CAS  PubMed  Google Scholar 

  123. Mempel, T.R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).

    CAS  PubMed  Google Scholar 

  124. Lalor, P.F. & Adams, D.H. Adhesion of lymphocytes to hepatic endothelium. Mol. Pathol. 52, 214–219 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Warren, A. et al. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44, 1182–1190 (2006).

    CAS  PubMed  Google Scholar 

  126. Xu, X.D. et al. Trafficking of recirculating lymphocytes in the rat liver: rapid transmigration into the portal area and then to the hepatic lymph. Liver Int. 28, 319–330 (2008).

    PubMed  Google Scholar 

  127. Valiante, N.M. et al. Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C. Immunol. Rev. 174, 77–89 (2000).

    CAS  PubMed  Google Scholar 

  128. Zeremski, M., Petrovic, L.M. & Talal, A.H. The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection. J. Viral Hepat. 14, 675–687 (2007).

    CAS  PubMed  Google Scholar 

  129. Hokeness, K.L. et al. CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection. J. Virol. 81, 1241–1250 (2007).

    CAS  PubMed  Google Scholar 

  130. Saunders, B.M. & Britton, W.J. Life and death in the granuloma: immunopathology of tuberculosis. Immunol. Cell Biol. 85, 103–111 (2007).

    PubMed  Google Scholar 

  131. Egen, J.G. et al. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28, 271–284 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Ben-Chetrit, E., Bergmann, S. & Sood, R. Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. Rheumatology (Oxford) 45, 274–282 (2006).

    CAS  Google Scholar 

  133. Aiello, R.J. et al. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler. Thromb. Vasc. Biol. 22, 443–449 (2002).

    CAS  PubMed  Google Scholar 

  134. Chiba, K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol. Ther. 108, 308–319 (2005).

    CAS  PubMed  Google Scholar 

  135. Barber, D.F. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat. Med. 11, 933–935 (2005).

    CAS  PubMed  Google Scholar 

  136. Wenzel, J., Uerlich, M., Haller, O., Bieber, T. & Tueting, T. Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod. J. Cutan. Pathol. 32, 257–262 (2005).

    PubMed  Google Scholar 

  137. Schon, M.P. & Schon, M. TLR7 and TLR8 as targets in cancer therapy. Oncogene 27, 190–199 (2008).

    CAS  PubMed  Google Scholar 

  138. Hauzenberger, D., Klominek, J. & Sundqvist, K.G. Functional specialization of fibronectin-binding beta 1-integrins in T lymphocyte migration. J. Immunol. 153, 960–971 (1994).

    CAS  PubMed  Google Scholar 

  139. Nemoto, E., Tada, H. & Shimauchi, H. Disruption of CD40/CD40 ligand interaction with cleavage of CD40 on human gingival fibroblasts by human leukocyte elastase resulting in down-regulation of chemokine production. J. Leukoc. Biol. 72, 538–545 (2002).

    CAS  PubMed  Google Scholar 

  140. Pasvolsky, R. et al. RhoA is involved in LFA-1 extension triggered by CXCL12 but not in a novel outside-in LFA-1 activation facilitated by CXCL9. J. Immunol. 180, 2815–2823 (2008).

    CAS  PubMed  Google Scholar 

  141. Van Vliet, E., Melis, M., Foidart, J.M. & Van Ewijk, W. Reticular fibroblasts in peripheral lymphoid organs identified by a monoclonal antibody. J. Histochem. Cytochem. 34, 883–890 (1986).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by Deutsche Forschungsgemeinschaft grant FR1155/6-3 (P.F.).

Author information

Authors and Affiliations

  1. Department of Cell Biology, Microscopical Imaging of the Cell, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, 6525GA Nijmegen, 6500 HB, Nijmegen, The Netherlands

    Peter Friedl & Bettina Weigelin

  2. Rudolf Virchow Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, Würzburg, 97080, Germany

    Peter Friedl & Bettina Weigelin

Authors
  1. Peter Friedl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bettina Weigelin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Friedl.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Table 1 (PDF 189 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Friedl, P., Weigelin, B. Interstitial leukocyte migration and immune function. Nat Immunol 9, 960–969 (2008). https://doi.org/10.1038/ni.f.212

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.f.212

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing